Written in Blood
Ibrutinib Plus R-ICE Induces Responses in Patients With Relapsed / Refractory DLBCL
A phase I study found that adding ibrutinib to R-ICE ( rituximab , ifosfamide , carboplatin , etoposide ) resulted in an overall response rate of 90 percent ( range = 68- 99 %) in patients with relapsed or refractory diffuse large B-cell lymphoma ( DLBCL ). Craig S . Sauter , MD , of the Division of Hematologic Oncology , Lymphoma Service at
Memorial Sloan Kettering Cancer Center in New York , and co-authors said the results were “ an encouraging signal of efficacy with … [ greater than ] 50 percent [ of patients ] achieving complete remission ( CR ).” The study ’ s findings were published in Blood .
“ In the post-rituximab era , approximately half [ of ] patients with relapsed or
VONVENDI [ von Willebrand factor ( Recombinant )] Brief Summary of Prescribing Information . Please see package insert for full Prescribing Information
INDICATIONS AND USAGE
VONVENDI [ von Willebrand factor ( Recombinant )] is a recombinant von Willebrand factor indicated for on-demand treatment and control of bleeding episodes in adults ( age 18 and older ) diagnosed with von Willebrand disease .
CONTRAINDICATIONS
VONVENDI is contraindicated in patients who have had life-threatening hypersensitivity reactions to VONVENDI or constituents of the product ( tri-sodium citrate-dihydrate , glycine , mannitol , trehalose-dihydrate , polysorbate 80 , and hamster or mouse proteins ).
WARNINGS AND PRECAUTIONS
Embolism and Thrombosis Thromboembolic reactions , including disseminated intravascular coagulation ( DIC ), venous thrombosis , pulmonary embolism , myocardial infarction , and stroke , can occur , particularly in patients with known risk factors for thrombosis . Monitor for early signs and symptoms of thrombosis such as pain , swelling , discoloration , dyspnea , cough , hemoptysis , and syncope .
In patients requiring frequent doses of VONVENDI with recombinant factor VIII , monitor plasma levels for FVIII : C activity because an excessive rise in factor VIII levels can increase the risk of thromboembolic complications .
Hypersensitivity Reactions Hypersensitivity reactions , including anaphylaxis , may occur . Symptoms can include anaphylactic shock , generalized urticaria , angioedema , chest tightness , hypotension , shock , lethargy , nausea , vomiting , paresthesia , pruritus , restlessness , wheezing and / or acute respiratory distress . If signs and symptoms of severe allergic reactions occur , immediately discontinue administration of VONVENDI and provide appropriate supportive care .
VONVENDI contains trace amounts of mouse immunoglobulin G ( MuIgG ) and hamster proteins less than or equal to 2 ng / IU VONVENDI . Patients treated with this product may develop hypersensitivity reactions to non-human mammalian proteins .
Neutralizing Antibodies Neutralizing antibodies ( inhibitors ) to von Willebrand factor and / or factor VIII can occur . If the expected plasma levels of VWF activity ( VWF : RCo ) are not attained , perform an appropriate assay to determine if anti-VWF or anti-FVIII inhibitors are present . Consider other therapeutic options and direct the patient to a physician with experience in the care of either von Willebrand disease or hemophilia A .
In patients with high levels of inhibitors to VWF or factor VIII , VONVENDI therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions . Since inhibitor antibodies can occur concomitantly with anaphylactic reactions , evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors .
Monitoring Laboratory Tests
• Monitor plasma levels of VWF : RCo and factor VIII activities in patients receiving VONVENDI to avoid sustained excessive von Willebrand factor and / or factor VIII activity levels , which may increase the risk of thrombotic events , particularly in patients with known clinical or laboratory risk factors .
• Monitor for development of von Willebrand factor and / or factor VIII inhibitors when suspected . Perform appropriate inhibitor assays to determine if von Willebrand factor and / or factor VIII inhibitors are present if bleeding is not controlled with the expected dose of VONVENDI .
ADVERSE REACTIONS
The most common adverse reaction observed in ≥2 % of subjects in clinical trials ( n = 66 ) was generalized pruritus .
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice . refractory DLBCL fail to achieve a chemosensitive response to standard salvage therapy and are thus ineligible to proceed to autologous [ hematopoietic ] cell transplantation ( AHCT ) with curative intent ,” the researchers explained . Based on results from an earlier trial in which ibrutinib demonstrated single-agent activity in this
The safety profile of VONVENDI was evaluated in three prospective , multicenter trials ; two were conducted in subjects with von Willebrand disease ( n = 66 ) and one was conducted in subjects with hemophilia A ( n = 12 ). The adverse reactions reported in the two von Willebrand disease trials are listed in Table 1 .
Table 1 : Summary of Adverse Reactions in Patients with von Willebrand Disease a
System Organ Class ( SOC )
Adverse Reaction a
This trial was done using ADVATE [ Antihemophilic factor ( Recombinant )], a recombinant factor VIII .
Immunogenicity
The immunogenicity of VONVENDI was assessed in clinical trials by assessing the development of neutralizing antibodies against rVWF and rFVIII , as well as binding antibodies against rVWF , rFurin , Chinese hamster ovary ( CHO ) protein and mouse IgG . No treatment-related development of binding or neutralizing antibodies against VWF or of neutralizing antibodies against FVIII was observed . Moreover , binding antibodies against potential impurities such as rFurin , CHO-protein or mouse IgG did not develop after treatment with VONVENDI .
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody ( including neutralizing antibody ) positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , it may be misleading to compare the incidence of antibodies to VONVENDI in the studies described above with the incidence of antibodies in other studies or to other products .
© 2017 Shire US Inc ., Lexington , MA 02421 . All rights reserved . 1-800-828-2088 . SHIRE and the Shire Logo are registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates . VONVENDI is a registered trademark of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc . Patented : see www . shire . com / legal-notice / product-patents
Shire Westlake Village , CA 91362 USA U . S . License No . 2020 Printed in USA Issued : 12 / 2015
S35819 10 / 17
Number of Subjects (%) ( n = 66 )
Number of Infusions (%) ( n = 355 )
Cardiac Disorders Tachycardia 1 ( 1.52 %) 1 ( 0.28 %)
Gastrointestinal Disorders
General Disorders and Administration Site Conditions
Skin and Subcutaneous Tissues Disorders
Vascular Disorder
Nervous System Disorders
Nausea 1 ( 1.52 %) 1 ( 0.28 %)
Infusion site paresthesia
1 ( 1.52 %) 1 ( 0.28 %)
Chest discomfort 1 ( 1.52 %) 1 ( 0.28 %)
Generalized pruritus
2 ( 3.03 %) 2 ( 0.56 %)
Hot flush 1 ( 1.52 %) 1 ( 0.28 %) Hypertension 1 ( 1.52 %) 2 ( 0.56 %) Dizziness 1 ( 1.52 %) 1 ( 0.28 %) Dysgeusia 1 ( 1.52 %) 1 ( 0.28 %) Tremor 1 ( 1.52 %) 1 ( 0.28 %)
Investigations Heart rate increase 1 ( 1.52 %) 1 ( 0.28 %)
Electrocardiogram T wave inversions 1 ( 1.52 %) 1 ( 0.28 %) setting , investigators conducted a singlecenter , dose-escalation study of ibrutinib plus R-ICE in transplant-eligible patients .
The trial enrolled 21 patients ( median age = 59 years ; range = 19-75 years ) with biopsy-confirmed CD20-positive DLBCL that relapsed after or was refractory to single-line R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , prednisone ) or similar therapies . Participants were required to have normal end-organ function , and those with HIV were eligible if they were on a stable antiretroviral regimen . Individuals were excluded if they had central nervous system involvement or serologic evidence of viral hepatitis .
“ [ This study ] confirms that ibrutinib in doses up to 840 mg daily combined with R-ICE is well tolerated , with no observed dose-limiting toxicities ...”
— CRAIG S . SAUTER , MD
Disease histology included de novo DLBCL ( n = 12 ; 57 %) – both germinal center ( GC ; n = 3 ; 14 %) and non-GC ( n = 9 ; 43 %) – primary mediastinal large B-cell lymphoma ( n = 4 ; 19 %), and Richter ’ s transformation ( n = 5 ; 24 %).
Patients received three cycles of R-ICE plus ibrutinib on days one to 21 of each cycle . Researchers used a 3 + 3 dosing design for ibrutinib , with patients receiving 420 , 560 , or 840 mg daily . All patients received growth factor support with either pegylated granulocyte-colony stimulating factor ( GCSF ) or daily GCSF with CD34- positive hematopoietic progenitor cell ( HPC ) harvest allowable after the second treatment cycle .
The researchers conducted an interim restaging evaluation with computed tomography after two cycles of therapy and full restaging after three cycles .
March 2018